Project Summary: NMR has contributed a long and rich history of molecular dynamics and equilibrium exchange measurements. Arguably, this is one of its greatest strengths. The combination of these aspects with in vivo imaging capabilities is potentially extremely powerful, and has already provided important physiological insights. The long-term objective of this project is to improve MRI methods to map equilibrium water molecular exchange across the blood-brain-barrier (BBB). This goal will be accomplished using conventional FDA-approved, low-molecular weight gadolinium contrast reagents (CRs) in human brain at 7 Tesla (T), and applying the comprehensive shutter-speed pharmacokinetic models developed in our laboratory that properly account for water exchanges between multiple tissue compartments as well as CR extravasation. This project takes advantage of the concurrent increase in the tissue water proton longitudinal relaxation time constant, and its dispersion, with magnetic field strength;a topic extensively studied by the PI and investigators. Taken together with the well-recognized S/N increases associated with increasing magnetic field, thus cause the CR detection limit to be greatly improved, which is crucial to this project. The use of a 7 T MRI instrument is expected to markedly improve the precision and accuracy of human brain parametric maps. In the normal brain, the trans-BBB permeability coefficients for water and CR (really, permeability surface area products) differ by four orders of magnitude (or more), and each is related to a different aspect of small vessel physiology. The overall goals of the proposed work are: a) to improve our MRI methods to obtain accurate and reliable human brain BBB water permeability maps, and b) to investigate sex dependences of BBB water permeability, and c) to investigate the association between BBB water permeability and multiple sclerosis (MS) disease expression. Relevance to Public Health: The control and regulation of brain water content is important in the progression of many diseases. The investigations proposed here will explore the novel, non-invasive MRI measurement of water exchange between blood and brain. This research will lead to a more complete understanding of water homeostasis in normal brain and how it is perturbed in MS. Emerging MS therapies have targeted BBB water transport proteins, and methods developed in this project will lead to non-invasive assessment of the efficacies of these interventions.